Nav: Home

Treatment reverses signs of 2 degenerative brain diseases, ALS and ataxia, in mice

April 12, 2017

Scientists report a significant step toward combatting two degenerative brain diseases that chip away at an individual's ability to move, and think. A targeted therapy developed by investigators at University of Utah Health slows the progression of a condition in mice that mimics a rare disease called ataxia. In a parallel collaborative study led by researchers at Stanford University, a nearly identical treatment improves the health of mice that model Amyotrophic Lateral Sclerosis (ALS), commonly called Lou Gehrig's disease.

The findings benchmark a new approach toward alleviating these previously untreatable conditions. In addition, they suggest that the therapy's target, the ataxin-2 gene, may be important for maintaining the health of brain cells. Additional work needs to be done to determine whether the regimen is safe and effective in humans and forestalls the death of brain cells over the long-term.

"This is a proof of concept that these new compounds could become the basis for new therapies for neurodegenerative disease, which so far have been largely impenetrable," says Stefan Pulst M.D., Dr Med, , chair of neurology at U of U Health, also senior author on the first study and a collaborator on the second. Both reports will be published online in the journal Nature on April 12, 2017.

At first glance, patients with a type of ataxia, called spinocerebellar ataxia type 2, appear drunk. They stumble, slur their speech and have trouble keeping balance. Patients are often puzzled by the odd collection of symptoms when they first appear, usually after they reach adulthood. But for Pulst, a neurologist, the signs raise alarm bells. They flag a genetic mutation that causes brain cells to die and symptoms to worsen over time.

"It is frustrating when I have to tell patients that there is no magic bullet," says Pulst. In the most severe cases, ataxia resembles ALS, making it difficult to swallow and eventually to breathe. "At this point there's nothing we can do to slow the pace of their disease."

In order to test experimental treatments, Pulst's team engineered mice that carry the human disease gene. Like their human counterparts, the rodents have many of the same signs of disease, including an overactive ataxin-2 gene that is toxic to brain cells. The scientists injected the rodents with small snippets of manufactured, modified DNA, called antisense oligonucleotides. Like a homing beacon, these compounds found instructions specified by the mutated gene and targeted them for destruction by natural processes.

In less than two months following treatment, mice performed significantly better on a balance and coordination test, an improvement that the scientists showed was more than skin deep. The brain's cerebellum, a region that coordinates movement, showed signs of restoration, too.

The activity of cells in the cerebellum, which had slowed considerably, returned to firing at normal rates after treatment. Further, expression of a handful of genes that had diminished during disease reverted back to normal.

"The antisense oligonucleotides are directly targeting the root cause of disease inside the cell, explaining why the mice recover some of their motor behavior," says lead author Daniel Scoles, Ph.D., associate professor of neurology at U of U health.

One injection directly into the brain lasted for more than four months, and mice did not have obvious side effects.

The idea of targeting errant disease genes with antisense oligonucleotide is not new. Recent advances in the technology, however, have increased their accuracy and enabled them to last longer in the body, making them more effective.

In a separate investigation, scientists were surprised to find that the same treatment using antisense oligonucleotides to target the ataxin-2 gene is also effective against an ALS-like condition in mice. Like ataxia, ALS is a neurodegenerative disease but it progresses much more rapidly. While many patients live with ataxia for decades following diagnosis, the life expectancy of patients with ALS is generally two to five years.

The therapy improved movement in mice with ALS and they survived considerably longer, with their lifespan increased by more than one-third. The ataxin-2 gene is not mutated in ALS, and so the treatment is believed to work by an indirect mechanism.

"Nearly all ALS cases are associated with accumulation of clumps of a protein called TDP-43. We have found a way to protect against the toxic consequences of this - by targeting the ataxin-2 gene," explains Aaron Gitler, Ph.D., associate professor of genetics at Stanford University and senior author of the ALS study. "If this works in humans and is safe, then we could potentially treat a large number of patients with ALS."

Additional research is being carried out to further understand how the therapy alleviates ALS in mice and determine whether targeting ataxin-2 may also work against other brain degenerative conditions with a similar pathology, such as frontotemporal dementia.

Pulst says that while much work remains to be done, he now faces his patients with a renewed optimism fueled in part by another recent development. In Dec. 2016, the FDA approved the first drug to slow a neurodegenerative condition, a childhood disease called spinal muscular atrophy. That medicine is also based on antisense oligonucleotides, demonstrating that the technology can effectively treat this class of disease in people.

"Our combined work is an example of how understanding a rare disease can impact more than the small number of people affected by it," says Pulst. "It is leading to insights into treatments for more common diseases."
-end-
In addition to Pulst and Scoles, additional researchers from University of Utah Health and from University of California, Los Angeles, and Ionis Pharmaceuticals co-authored the ataxia study, published as "Antisense oligonucleotide therapy for spinocerebellar ataxia type 2" in Nature.

Gitler, Pulst, and scientists from Stanford University, Ionis Pharmaceuticals, St. Jude's Research Hospital, and Goethe University, Germany, co-authored the ALS study, published as "Therapeutic reduction of ataxin 2 extends the lifespan and rescues pathological features of ALS and TDP-43 transgenic mice" in Nature.

The ataxia research was supported by funding from the National Institutes of Neurological Disorders and Stroke, the Noorda Foundation, Target ALS Foundation, and a gift from Ionis Pharmaceuticals. The ALS study was supported by the National Institutes of Health, Target ALS Foundation, National Science Foundation, Robert Packard Center for ALS Research at Johns Hopkins, Glenn Foundation, and the DFG grant.

University of Utah Health

Related Brain Articles:

Transplanting human nerve cells into a mouse brain reveals how they wire into brain circuits
A team of researchers led by Pierre Vanderhaeghen and Vincent Bonin (VIB-KU Leuven, Université libre de Bruxelles and NERF) showed how human nerve cells can develop at their own pace, and form highly precise connections with the surrounding mouse brain cells.
Brain scans reveal how the human brain compensates when one hemisphere is removed
Researchers studying six adults who had one of their brain hemispheres removed during childhood to reduce epileptic seizures found that the remaining half of the brain formed unusually strong connections between different functional brain networks, which potentially help the body to function as if the brain were intact.
Alcohol byproduct contributes to brain chemistry changes in specific brain regions
Study of mouse models provides clear implications for new targets to treat alcohol use disorder and fetal alcohol syndrome.
Scientists predict the areas of the brain to stimulate transitions between different brain states
Using a computer model of the brain, Gustavo Deco, director of the Center for Brain and Cognition, and Josephine Cruzat, a member of his team, together with a group of international collaborators, have developed an innovative method published in Proceedings of the National Academy of Sciences on Sept.
BRAIN Initiative tool may transform how scientists study brain structure and function
Researchers have developed a high-tech support system that can keep a large mammalian brain from rapidly decomposing in the hours after death, enabling study of certain molecular and cellular functions.
Wiring diagram of the brain provides a clearer picture of brain scan data
In a study published today in the journal BRAIN, neuroscientists led by Michael D.
Blue Brain Project releases first-ever digital 3D brain cell atlas
The Blue Brain Cell Atlas is like ''going from hand-drawn maps to Google Earth'' -- providing previously unavailable information on major cell types, numbers and positions in all 737 brain regions.
Landmark study reveals no benefit to costly and risky brain cooling after brain injury
A landmark study, led by Monash University researchers, has definitively found that the practice of cooling the body and brain in patients who have recently received a severe traumatic brain injury, has no impact on the patient's long-term outcome.
Brain cells called astrocytes have unexpected role in brain 'plasticity'
Researchers from the Salk Institute have shown that astrocytes -- long-overlooked supportive cells in the brain -- help to enable the brain's plasticity, a new role for astrocytes that was not previously known.
Largest brain study of 62,454 scans identifies drivers of brain aging
In the largest known brain imaging study, scientists from Amen Clinics (Costa Mesa, CA), Google, John's Hopkins University, University of California, Los Angeles and the University of California, San Francisco evaluated 62,454 brain SPECT (single photon emission computed tomography) scans of more than 30,000 individuals from 9 months old to 105 years of age to investigate factors that accelerate brain aging.
More Brain News and Brain Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Uncharted
There's so much we've yet to explore–from outer space to the deep ocean to our own brains. This hour, Manoush goes on a journey through those uncharted places, led by TED Science Curator David Biello.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Dispatch 2: Every Day is Ignaz Semmelweis Day
It began with a tweet: "EVERY DAY IS IGNAZ SEMMELWEIS DAY." Carl Zimmer – tweet author, acclaimed science writer and friend of the show – tells the story of a mysterious, deadly illness that struck 19th century Vienna, and the ill-fated hero who uncovered its cure ... and gave us our best weapon (so far) against the current global pandemic. This episode was reported and produced with help from Bethel Habte and Latif Nasser. Support Radiolab today at Radiolab.org/donate.